This is a Phase I SBIR Application entitled Isolation and Characterization of Low Molecular Weight Compounds Derived from Plant Extracts that Activate the IRS-2 Dependent Insulin Signaling Cascade. Diabetes is a growing and significant global health concern. Insulin Receptor Substrate-2 (IRS-2) is a critical component in the insulin mediated signal transduction cascade which regulates glucose and lipid metabolism, insulin sensitivity, and the growth, function and survival of insulin-producing beta cells. Molecules that activate IRS-2 have the potential to help maintain glucose metabolism, increase insulin sensitivity, and increase insulin secretion by enhancing the function and viability of ?-cells. HPRL previously developed an IRS-2-specific assay system to identify leads that activate ectopically overproduced IRS-2 in 32DIRS-2 cells while having no effect on control 32D cells which lack detectable IRS-2. Using this cell-based assay, we have discovered novel plant extracts that activate IRS-2 signaling in 32DIRS-2 cells. HPRL has filed patents describing plant extracts with insulin-like, IRS-2 activating pharmacological properties. One of these plant extracts, now designated HP-211, activates the IRS-2 signal transduction cascade. HP-211 exhibits ?100% of the IRS-2 signaling activity as compared to Insulin in cell- based assays in vitro. Preliminary in vivo efficacy and safety data for this extract in mice demonstrate that HP-211 is at least as effective as metformin in a short term studies. SBIR funding is requested to enable the isolation and characterization one or more of the active natural product compounds from HP-211 that activate IRS-2 signaling. In Phase II, we intend to further investigate the safety and efficacy of the isolated natural product compounds with a goal of developing a therapeutic treatment for diabetes and related metabolic disorders. Compounds isolated from HP-211 will comprise a significant and innovative new area of therapeutic discovery with great potential to treat and possibly even prevent metabolic disorders such as diabetes.